Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic

Nature Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract SARS-CoV-2 variants are mainly defined by mutations in their spike. It is therefore critical to understand how the evolutionary trajectories of spike affect virus phenotypes. So far, it has been challenging comprehensively compare many spikes that emerged during pandemic a single experimental platform. Here we generated panel recombinant viruses carrying different proteins from 27 circulating between 2020 and 2024 same genomic background. We then assessed several phenotypic traits both vitro vivo. found distinct among before after emergence Omicron variants. Spike post-Omicron maintained enhanced tropism for nasal epithelium large airways but displayed, over time, typical pre-Omicron Hence, with features pre- may continue emerge future.

Language: Английский

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Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)

Published: April 1, 2024

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding spike protein. In contrast, whether antigenic occurs S2 remains largely elusive. Here, we perform a deep mutational scanning experiment to identify that affect three apex public antibodies. Our results indicate spatially diverse mutations, including D950N Q954H, which are observed Delta Omicron variants, respectively, weaken these Although antibodies known be nonneutralizing, show they confer protection vivo through Fc-mediated effector functions. Overall, this study indicates can undergo drift, represents potential challenge for development more universal coronavirus vaccines.

Language: Английский

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A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(9), P. e3002767 - e3002767

Published: Sept. 24, 2024

Interferons (IFNs) play a crucial role in the regulation and evolution of host–virus interactions. Here, we conducted genome-wide arrayed CRISPR knockout screen presence absence IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis interacting with SARS-CoV-2, drawing from selection 67 large-scale studies, including our own. identified 28 high relevance both genetic studies Disease 2019 (COVID-19) patients functional screens cell culture, many related pathway. Among these was IFN-stimulated gene PLSCR1 . did not require induction restrict SARS-CoV-2 contribute signaling. Instead, specifically restricted spike-mediated entry. The PLSCR1-mediated restriction alleviated by TMPRSS2 overexpression, suggesting primarily restricts endocytic entry route. In addition, recent variants have adapted circumvent barrier via currently undetermined mechanisms. Finally, investigate effects present humans discuss association between severe COVID-19 reported recently.

Language: Английский

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Host Membranes as Drivers of Virus Evolution

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1854 - 1854

Published: Aug. 31, 2023

The molecular mechanisms controlling the adaptation of viruses to host cells are generally poorly documented. An essential issue resolve is whether membranes, and especially lipid rafts, which usually considered passive gateways for many enveloped viruses, also encode informational guidelines that could determine virus evolution. Due their enrichment in gangliosides confer an electronegative surface potential, rafts impose a first control level favoring selection with enhanced cationic areas, as illustrated by SARS-CoV-2 variants. Ganglioside clusters attract viral particles dynamic electrostatic funnel, more population winning race. However, forces account only small part energy raft-virus interaction, depends mainly on ability form network hydrogen bonds raft gangliosides. This fine tuning virus-ganglioside interactions, stabilize membrane, generates second pressure driven typical induced-fit mechanism. Gangliosides play active role this process, wrapping around spikes through quicksand-like Viruses thus endless race access they bound evolve perpetually, combining speed (electrostatic potential) precision (fine amino acids) under selective immune system. Deciphering membrane evolution may open new avenues design innovative antivirals.

Language: Английский

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Molecular and structural insights into SARS-CoV-2 evolution: from BA.2 to XBB subvariants

mBio, Journal Year: 2024, Volume and Issue: 15(10)

Published: Sept. 16, 2024

ABSTRACT Due to the incessant emergence of various SARS-CoV-2 variants with enhanced fitness in human population, controlling COVID-19 pandemic has been challenging. Understanding how virus enhances its during a could offer valuable insights for more effective control viral epidemics. In this manuscript, we review evolution from early 2022 end 2023—from Omicron BA.2 XBB descendants. Focusing on period, provide concrete examples that increased by enhancing several functions spike (S) protein, including binding affinity ACE2 receptor and ability evade humoral immunity. Furthermore, explore specific mutations modify these S protein through structural alterations. This provides evolutionary, molecular, into repeatedly caused epidemic surges pandemic.

Language: Английский

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Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein and potentially drive the genesis of Omicron variants

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 31, 2024

Abstract Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population genesis virus has long been suggested but its molecular basis remains poorly understood. Here, we identify a class neutralizing public antibodies defined their shared usage VL6-57 light chains. Although heavy chains diverse genotypes are utilized, convergent HCDR3 rearrangements have observed among these cooperate with germline LCDRs target epitope RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this is present in SARS-CoV-2-naive individuals clonally expanded most COVID-19 patients. We confirm Omicron-specific substitutions at S371, S373 S375 mediate escape the class. These findings support constitutes potential immune pressure promoting introduction S371L/F-S373P-S375F Omicron variants. The results provide further evidence antigenic driven mediated immunity.

Language: Английский

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Circulating neutralizing antibodies and SARS-CoV-2 variant replication following postvaccination infections

JCI Insight, Journal Year: 2025, Volume and Issue: 10(5)

Published: March 9, 2025

The effect of preexisting neutralizing antibodies (NAb) on SARS-CoV-2 shedding in postvaccination infection (PVI) is not well understood. We characterized viral longitudinally nasal specimens relation to baseline (pre/periinfection) serum NAb titers 125 participants infected with variants. Among 68 vaccinated participants, we quantified the maximum RNA and infectivity duration. Baseline NAbs were higher targeted a broader range variants monovalent ancestral booster vaccinations compared those primary vaccine series. In Delta infections, targeting or Wuhan-Hu-1 correlated negatively RNA. Per log10 increase Delta-targeting IC50, load was reduced -2.43 (95% CI: -3.76, -1.11) nucleocapsid copies, infectious -2.79 -4.99, -0.60) days. Conversely, Omicron infections (BA.1, BA.2, BA.4, BA.5), against lineages did predict outcomes. Our results provide robust estimates magnitude duration replication after PVI (albeit an unclear transmission) show how immune escape efficiently evade these modulating effects.

Language: Английский

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Monitoring reported SARS-CoV-2 variants to assess the status of COVID-19 epidemics in the low epidemic state

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 24, 2025

The reported new confirmed cases of Coronavirus Disease 2019 (COVID-19) nowadays have diminished in their usefulness for assessing the pandemic situation. This study aimed to discover correlation Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) variants recorded by Nextstrain clade and PANGO lineage number cases. Percent stacked area charts were utilized display development trends. 31 1452 named according lineage, respectively. branch step value maintained a stable increase linear regression analysis. changing trend SARS-CoV-2 (PANGO lineage) correlated negatively with COVID-19 through Spearman rank coefficient (17/06/2020-17/11/2021, ρ=-0.387, P < 0.01; 15/12/2021-11/01/2023, ρ=-0.458, 0.01). proportion composition dominant virus had regional discrepancies, but some also fluctuated. speed quantity objectively reflect characteristics viral dissemination population even without valuable data variation may be better tool epidemic monitoring early-warning low state.

Language: Английский

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CRISPR-Cas9 genetic screens reveal regulation of TMPRSS2 by the Elongin BC-VHL complex

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 7, 2025

Abstract The TMPRSS2 cell surface protease is used by a broad range of respiratory viruses to facilitate entry into target cells. Together with ACE2, represents key factor for SARS-CoV-2 infection, as mediates cleavage viral spike protein, enabling direct fusion the envelope host membrane. Since start COVID-19 pandemic, has gained attention therapeutic inhibitors which would inhibit but little known about regulation, particularly in types physiologically relevant infection. Here, we performed an unbiased genome-wide CRISPR-Cas9 library screen, together targeted at epigenetic modifiers and transcriptional regulators, identify cellular factors that modulate expression human colon epithelial We find endogenous regulated Elongin BC-VHL complex HIF transcription factors. Depletion B or treatment cells PHD resulted downregulation inhibition show still utilised Omicron variants colonic Our study enhances our understanding regulation

Language: Английский

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The nasal microbiome modulates risk for SARS-CoV-2 infection

EBioMedicine, Journal Year: 2025, Volume and Issue: unknown, P. 105660 - 105660

Published: April 1, 2025

The nasal microbiome may influence host risk for COVID-19 by modulating the expression of key proteins that facilitate SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2), which binds virus, and transmembrane serine protease (TMPRSS2), activates viral entry into epithelial cells. This study examined whether levels ACE2 TMPRSS2 in cavity predict infection modulates their expression. Using 1548 self-collected swabs from a population-based surveillance testing community-dwelling adults Washington D.C., we conducted two retrospective case-control studies (cross-sectional: n = 111 cases 343 controls; longitudinal: 97 cases, 286 controls) (n 428). Cases, defined as individuals with positive test, were matched controls based on age test date. Pre-infection samples analysed. We measured ACE2/TMPRSS2 using RT-qPCR characterized 16S rRNA gene-based qPCR sequencing. used machine learning regression analysis to determine if predicts influences Elevated was associated 3.6-fold increased contracting (95% CI 1.71-7.47) compared those no detectable or TMPRSS2. Before SARS-CoV-2, also had significantly higher more unstable than controls. Having high densities Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis/nonliquefaciens linked In contrast, having Dolosigranulum pigrum decreased These results suggest natural variation impacts near-term adults. Modifying could potentially reduce risk. Research reported this article supported Milken Institute School Public Health, George University National Allergy Infectious Diseases, Institutes Health under award number R01AI168182. content is solely responsibility authors does not necessarily represent official views Health.

Language: Английский

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